The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease

Abstract

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing cytosolic damage-associated molecular patterns (DAMPs), and inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation of this pathway culminates in AD-related neuroinflammation and neurodegeneration. A substantial body of evidence indicates that mitochondria are involved in the critical pathogenic mechanisms of AD, whose damage leads to the release of mitochondrial DNA (mtDNA) into the extramitochondrial space. This leaked mtDNA serves as a DAMP, activating various pattern recognition receptors and immune defense networks in the brain, including the cGAS-STING pathway, ultimately leading to an imbalance in immune homeostasis. Therefore, modulation of the mtDNA-cGAS-STING pathway to restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In this review, we focus on the mechanisms of mtDNA release during stress and the activation of the cGAS-STING pathway. Additionally, we delve into the research progress on this pathway in AD, and further discuss the primary directions and potential hurdles in developing targeted therapeutic drugs, to gain a deeper understanding of the pathogenesis of AD and provide new approaches for its therapy.